Despite the presence of HIV-specific cytotoxic T cells and virus-specific antibodies, HIV reservoirs persist in lymphoid tissues in HIV infected individuals and pose obstacles for HIV cure. Clues may lie in the early pathogenic effects of HIV infection in the secondary lymphoid tissues including gut lymphoid tissue and disruption of their structure and function. Novel combination approaches are needed for targeting eradication of virally infected cells. The overall objective of this proposed R01 application is to investigate the potential of mesenchymal stromal/stem cells (MSC) in enhancing mucosal anti-viral immunity and to determine efficacy of viral suppression in combination with ART as well as the viral clearance in combination with eCD4-Ig, an HIV and SIV inhibitor. We propose to utilize SIV infected non-human primate model of AIDS to investigate potential therapeutic benefits of MSCs in combination with eCD4-Ig or ART for effective clearance of virally infected cells. MSCs are adult stem cells that are anti-inflammatory and immunomodulatory and are investigated as therapeutics. Our preliminary results of MSC administration in SIV infected rhesus macaque model of AIDS showed redistribution of SIV infected cells to lymphoid follicles and enhanced anti-viral immunity. This opens a new opportunity to corral and target the virus by using a combination of MSC and a novel potent viral inhibitor, eCD4-Ig and reduce the viral pool from GALT. We will test the hypothesis that systemic MSC administration will modulate antigen presentation and enhance anti-viral immunity at mucosal sites in SIV infected rhesus macaque model of AIDS and lead to better viral suppression and increased immune recovery. This proposal leverages on our unique strengths in MSC biology, SIV model of AIDS, mucosal immunology and novel eCD4-Ig inhibitor. The overall objective of this R01 proposal is to investigate the effects of MSC administration on anti-viral mucosal immunity and viral clearance in gut lymphoid tissue of SIV infected rhesus macaques. Aim 1: To determine the effect of MSC administration on anti-viral mucosal immunity and viral clearance in gut lymphoid tissue of SIV infected rhesus macaques. MSC will be injected into chronically SIV infected animals and its effect on anti-viral mucosal immunity and viral clearance in gut lymphoid tissue and peripheral blood will be examined. Efficacy of AAV-expressed eCD4-Ig in combination with MSC administration will be examined for eradicating virus-positive cells and viral loads. Aim 2: To determine the effect of MSC administration on effective viral suppression in gut lymphoid tissue during ART as well as after ART interruption. SIV infected macaques on ART will receive MSC during ART and after ART interruption and virologic, immunologic and molecular analyses will be performed. The proposed study will provide an innovative approach of using MSC to enhance anti-viral immunity, resolve virus-associated mucosal damage and induce effective viral suppression and clearance.